4tpm
From Proteopedia
Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as PDE10A Inhibitors
Structural highlights
FunctionPDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedWe report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum. Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.,Rzasa RM, Frohn MJ, Andrews KL, Chmait S, Chen N, Clarine JG, Davis C, Eastwood HA, Horne DB, Hu E, Jones AD, Kaller MR, Kunz RK, Miller S, Monenschein H, Nguyen T, Pickrell AJ, Porter A, Reichelt A, Zhao X, Treanor JJ, Allen JR Bioorg Med Chem. 2014 Oct 22;22(23):6570-6585. doi: 10.1016/j.bmc.2014.10.013. PMID:25456383[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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